Abstract

Dementia, a major cause of disability and institutionalization in older people, poses
a serious threat to public health and to the social and economic development of modern
society. Alzheimer's disease (AD) and cerebrovascular diseases are the main causes
of dementia; most dementia cases are attributable to both vascular and neurodegenerative
brain damage. No curative treatment is available, but epidemiological research provides
a substantial amount of evidence of modifiable risk and protective factors that can
be addressed to prevent or delay onset of AD and dementia. Risk of late-life dementia
is determined by exposures to multiple factors experienced over the life course, and
the effect of specific risk/protective factors depends largely on age. Moreover, cumulative
and combined exposure to different risk/protective factors can modify their effect
on dementia/AD risk. Multidisciplinary research involving epidemiology, neuropathology,
and neuroimaging has provided sufficient evidence that vascular risk factors significantly
contribute to the expression and progression of cognitive decline (including dementia)
but that active engagement in social, physical, and mentally stimulating activities
may delay the onset of dementia. However, these findings need to be confirmed by randomized
controlled trials (RCTs). A promising strategy for preventing dementia is to implement
intervention programs that take into account both the life-course model and the multifactorial
nature of this syndrome. In Europe, there are three ongoing multidomain interventional
RCTs that focus on the optimal management of vascular risk factors and vascular diseases.
The RCTs include medical and lifestyle interventions and promote social, mental, and
physical activities aimed at increasing the cognitive reserve. These studies will
provide new insights into prevention of cognitive impairment and dementia. Such knowledge
can help researchers plan larger, international prevention trials that could provide
robust evidence on dementia/AD prevention. Taking a step in this direction, researchers
involved in these European RCTs recently started the European Dementia Prevention
Initiative, an international collaboration aiming to improve strategies for preventing
dementia.

Introduction

Dementia is an acquired disabling syndrome characterized by progressive deterioration
in multiple cognitive domains and is severe enough to interfere with daily functioning.
Alzheimer's disease (AD) is the most common cause of dementia, but increasing evidence
from population-based neuropathological and neuroimaging studies shows that mixed
brain pathologies (neurodegenerative and vascular) account for most dementia cases,
especially in very old people [1,2].

Both prevalence and incidence of dementia rise exponentially with advancing age, and
70% of all dementia cases occur in people who are at least 75 years old [3]. The worldwide increase in the number of older adults, more pronounced in those who
are at least 80 years old, explains the epidemic proportions assumed by dementia.
Because dementia is a major cause of disability in and institutionalization of older
people, the increased prevalence of this syndrome places enormous pressures on health-care
systems and society. The World Alzheimer Report estimates that, in 2010, the number of people with dementia worldwide was 35.6 million
and that this will increase to 65.7 million by 2030 and 115.4 million by 2050 unless
effective means of reducing the incidence of this disease are introduced [4]. In 2010, the total estimated worldwide costs of dementia were USD $604 billion,
including the costs of informal care (unpaid care provided by family and others),
direct costs of social care (provided by community care professionals and in residential
home settings), and the direct costs of medical care (the costs of treating dementia
and other conditions in primary and secondary care) [4].

No curative treatment is available, but epidemiological research provides substantial
evidence of modifiable risk and protective factors that can be addressed to prevent
or delay AD and dementia onset. In this review, we summarize the evidence supporting
dementia/AD prevention and discuss key aspects that need to be considered when planning
preventive strategies.

Prevention of dementia: current evidence from observational studies

Over the last decades, the etiology of dementia has been extensively studied with
the aim of identifying efficacious prevention and treatment strategies. These efforts
have led to the broad consensus that dementia is a multi-factorial disorder caused
by several interrelated mechanisms in which the interaction of genetic and environmental
factors plays the major role (Table 1).

The pathways that lead from different risk factors to dementia are not fully understood,
but several etiological hypotheses have been proposed: the vascular hypothesis, inflammatory
hypothesis, oxidative stress hypothesis, toxic hypothesis, and psychosocial hypothesis
[5,6]. These theories highlight potential links of various risk factors to both the vascular
and the neurodegenerative brain pathologies that can cause dementia, justifying the
validity of dementia syndrome as target for prevention [7,8].

A recent report commissioned by the National Institutes of Health (NIH) and issued
by the Agency for Healthcare Research and Quality (AHRQ) concluded that current research
evidence on many risk and protective factors for cognitive decline and AD is not of
sufficient strength, thus recommendations for preventing these conditions cannot be
made [9,10]. Another previous review yielded similar conclusions [11]. These negative perspectives have been criticized since epidemiological evidence
that the use of antihypertensive medications, cessation of smoking, and increasing
physical activity produce cognitive benefits in older adults is not inadequate [12], and the analytical strategy used in the evidence-based review did not take into
account the life-course perspective [13]. In fact, observational longitudinal studies clearly show that the risk of late-life
dementia is determined by exposures to multiple factors experienced over the life
span and that the effect of specific risk/protective factors depends largely on age.
Thus, a life-course perspective is relevant for chronic disorders (such as dementia)
that have a long latent period. It allows the identification of time windows when
exposures have their greatest effect on outcome and assessment of whether cumulative
exposures could have multiplicative or additive effects over the life course [6].
Age-dependent associations with dementia/AD have been suggested for several aging-related
medical conditions. For example, elevated blood pressure, body mass index (BMI), and
total cholesterol levels at a young age and in middle age (< 65 years) are associated
with an increased risk of dementia and AD, and having lower values in late life (>
75 years) is also associated with subsequent development of dementia/AD [14-19]. Diabetes mellitus has been associated with increased risk of dementia and AD over
adult life, but the risk is stronger when diabetes occurs in mid-life than in late-life
[20]. Current smoking is another major risk factor for dementia and AD, and, given the
worldwide prevalence of smoking, about 14% of all AD cases are potentially attributable
to this risk factor [21]. Although it is not entirely clear whether depression is a risk factor for or a preclinical
symptom of dementia, studies with long-term follow-up support the risk factor hypothesis
[22].

Protective factors for dementia and AD have also been identified; these include high
education and socioeconomic status in early life as well as a number of factors in
adult life: high work complexity, rich social network, social engagement, mentally
stimulating activity, nonsmoking, and regular physical exercise [5,23,24]. Living with a partner during mid-life has been associated with reduced risk of cognitive
impairment and dementia later in life, suggesting that being in a relationship entails
cognitive and social challenges that can increase the cognitive reserve [25]. Even at old ages, the active engagement in mental, physical, and social activities
may postpone the onset of dementia, possibly by increasing the cognitive reserve [26].

In addition, several follow-up studies reported a decreased dementia risk associated
with healthy dietary patterns and nutritional factors, such as high adherence to a
Mediterranean diet or dietary intake of antioxidants (for example, vitamins E and
C) and ω-3 polyunsaturated fatty acid (PUFA) (often measured as fish consumption)
[27-31].

Cumulative and combined exposure to different risk factors can lead to modified effects
on dementia/AD risk (Table 1). In the Finnish CAIDE (Cardiovascular Risk Factors, Aging and Incidence of Dementia)
study, the risk of dementia has been evaluated in relation to a score (CAIDE Dementia
Risk Score) combining mid-life risk factors, including low education and cardiovascular
factors (that is, hypertension, obesity, hypercholesterolemia, and physical inactivity).
The risk of dementia increased as the score increased in a dose-response trend, making
it possible to identify individuals who can greatly benefit from preventive intervention
that targets vascular risk factors [32]. Similar findings have been reported for late-life exposures: in the Swedish Kungsholmen
Project, the cumulative effect of vascular risk factors and vascular diseases on dementia/AD
risk has been investigated in people who are at least 75 years old. These factors
were aggregated according to two pathophysiological hypotheses: the brain hypoperfusion
profile, defined by chronic heart failure, low pulse pressure, and low diastolic pressure,
and the atherosclerosis profile, which included high systolic pressure, diabetes mellitus
or prediabetes, and stroke. In both profiles, dementia/AD risk increased with increasing
scores in a dose-response manner, suggesting a synergy of vascular risk factors in
promoting dementia/AD also in advanced age [33]. The American Cardiovascular Health Cognition Study developed a Late-life Dementia
Risk Index and also a brief version, which groups older adults in the three categories
of low, moderate, and high risk of developing dementia. Both versions of the index
support the cumulative effect of different factors in determining the risk of dementia
after the age of 65 years. These indices include information from different domains,
including demographic factors (age), genetics (presence of the apolipoprotein E (ApoE)
ε4 allele), lifestyle (BMI of less than 18.5 and lack of alcohol consumption), comorbid
vascular conditions (internal carotid artery thickening, angina, coronary artery bypass
surgery, stroke, and peripheral artery disease), evidence of brain abnormalities shown
by magnetic resonance imaging (white matter diseases or enlarged ventricles), cognitive
test scores, and physical performances [34,35].

The combined effect of genetic-environmental or environmental-environmental joint
exposures may also lead to the attenuation of the dementia risk. Population-based
studies suggest an effect modification for the ApoE ε4 allele, the most important
genetic risk factor for sporadic AD. ApoE ε4 carriers seem more vulnerable to risk
factors like alcohol drinking, smoking, physical inactivity, and high intake of saturated
fat, indicating that people with genetic susceptibility may reduce their initial AD
risk by lifestyle interventions (that is, physical activity, sufficient intake of
PUFA, and avoiding excess alcohol drinking and smoking) [36]. Furthermore, it has been shown that high education may reduce dementia risk among
ApoE ε4 allele carriers [37]. In regard to the interactions among modifiable risk factors, results from the Kungsholmen
Project suggested that complexity of work with data and people was related to a decreased
dementia risk and that the highest level of work complexity may modulate the increased
dementia risk due to low education [23].

In conclusion, even though for some risk and protective factors the role in dementia
and AD needs to be clarified, evidence from observational studies points at different
modifiable factors that can be managed in order to prevent or delay dementia onset.
Moreover, epidemiological findings strongly suggest that the life-course approach
model and the multifactorial nature of dementia and AD should be considered when planning
any preventive strategy.

Prevention of dementia: current evidence from interventional studies

Interventional studies on dementia and AD prevention have tested different medications,
including statins, antihypertensive drugs, estrogens alone or in combination with
progestin (hormone replacement therapy, or HRT), non-steroidal anti-inflammatory drugs
(NSAIDs), and nutraceuticals (folate, Ginkgo biloba, and vitamins B12, C, and E). For all of these compounds, the protective effects suggested by observational
studies have not been confirmed in randomized controlled trials (RCTs), the results
of which are inconsistent or even suggest a detrimental effect on cognition (for example,
NSAIDs and HRT) [38-41]. Few interventional studies implementing non-pharmacological approaches have been
carried out. Among them, some RCTs on cognitive training and physical activity provided
encouraging results, which need confirmation [38,42]. It is possible that the negative results from the RCTs done so far reflect the real
inefficacy of the tested strategies in preventing dementia and AD. However, the apparent
contradiction of results from observational and interventional studies could be explained
by several factors:

1. The intervention was done outside the time window during which management of a
risk factor would reduce dementia risk: several risk factors exert their effect mainly
during mid-life, whereas RCTs have been done in older adults. This is the case for
vascular risk factors, which seem to be more relevant when the exposure occurs during
mid-life. Moreover, the HRT research suggests that estrogens may have beneficial,
neutral, or detrimental effects on the brain depending on age at treatment, type of
menopause (natural versus medically or surgically induced), or stage of menopause
[43]. This concept, called the 'window of opportunity hypothesis', is in agreement with
the life-course approach model. There is evidence of neuroprotective effects of estrogens
in women before the age of natural menopause and in the early postmenopausal stage
(50 to 60 years), whereas estrogens initiated in late post-menopause (65 to 79 years)
increase the risk of cognitive impairment and dementia [43,44]. Two RCTs are ongoing and both are due to be completed this year; one is testing
the effect of HRT in early post-menopause (Kronos Early Estrogen Prevention Study,
or KEEPS; ClinicalTrials.gov identifier NCT00623311) and the other is comparing the
effects of HRT in early and late postmenopause (Early Versus Late Intervention Trial
With Estradiol, or ELITE; ClinicalTrials.gov identifier NCT00114517).

2. Short treatment and follow-up: many studies were of relatively short length. Thus,
interventions have been implemented for a period that is not long enough to determine
a neuroprotective effect, and the limited follow-up duration of many RCTs would not
allow detection of differences in dementia incidence.

3. The statistical power was inadequate since some RCTs had small samples and dementia
has been considered a secondary endpoint in most clinical trials (for example, antihypertensive
therapy).

4. The choice of compounds tested in RCTs using nutraceuticals was not optimal: although
several products have been tested, supplement composition is still a debated issue.
For instance, whereas observational studies suggested that a balanced intake of different
forms of vitamin E can be important for reducing dementia/AD risk, only one form (α-tocopherol)
has been tested in RCTs, and the findings were conflicting [29,30,45,46]. Moreover, intake of high doses of α-tocopherol supplements has been associated with
increased hemorrhagic stroke and mortality risk [47].

5. Despite the multifactorial nature of dementia and the importance of combined risk
exposures, most studies were based on a mono-intervention approach, almost always
testing single agents or lifestyle interventions. In multifactorial conditions, a
small reduction in multiple risk factors can substantially decrease overall risk.

In summary, despite the discrepancies between findings of observational and interventional
studies and the disappointing results of intervention studies on dementia and AD,
methodological issues of the RCTs carried out thus far suggest that a valid evaluation
of the efficacy of preventive measures has yet to be undertaken.

Prevention of dementia: ongoing multidomain intervention studies

The knowledge derived from the previously described observational and interventional
studies paved the way for some ongoing RCTs on the prevention of cognitive decline
and dementia. In Europe, there are three large ongoing RCTs: the Finnish Geriatric
Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), the Multidomain
Alzheimer Preventive Trial (MAPT), and the Prevention of Dementia by Intensive Vascular
Care (PreDIVA) study [48,49]. The common denominator of these studies is the multidomain approach, which aims
to simultaneously target several risk factors for dementia in older adults, mainly
by promoting lifestyle changes and adherence to medical treatments for vascular risk
factors and vascular diseases. All RCTs exclude individuals with dementia and use
clinical evaluation and neuropsychological tests to detect cognitive changes and dementia
incidence as main outcomes. Furthermore, secondary outcomes include functional status,
mood disorders, quality of life, adherence to the intervention programs, and utilization
of health resources. The latter two aspects are essential from a public health perspective
since they provide information on feasibility and cost-effectiveness of prevention
strategies. Additionally, both FINGER and MAPT include ancillary studies on neuroimaging
(morphological and functional), cerebrospinal fluid, and blood markers related to
AD pathophysiology in order to investigate the effect of the interventions on brain
morphology and metabolism, clarify mechanisms underlying preventive measures, and
identify biomarkers that can be used to monitor effects of interventions.

FINGER (ClinicalTrials.gov identifier NCT01041989) is a multicenter RCT aiming to
prevent cognitive impairment, dementia, and disability in 60- to 77-year-olds. The
study population is represented by 1,200 individuals who are at increased risk of
dementia and who were selected according to the CAIDE Dementia Risk Score and the
CERAD neuropsychological test battery [32,48]. The 2-year multidomain intervention includes nutritional guidance, physical activity,
cognitive training, increased social activity, and intensive monitoring and management
of metabolic and vascular risk factors (hypertension, dyslipidemia, obesity, and impaired
glucose tolerance). Individuals in the reference group are given general public health
advice on lifestyle and vascular risk factors. FINGER participants are recruited from
previous population-based observational surveys (that is, FINRISK and FIN-D2D) with
detailed retrospective information on lifestyle and vascular factors [48]. Thus, differences in these variables can be taken into account and this is normally
not possible in RCTs. The primary outcome is cognitive decline measured by a sensitive
Neuropsychological Test Battery and the Stroop and Trail-making tests, which can depict
early cognitive impairment typical for AD and vascular dementia (VaD). The planned
7-year extended follow-up will allow detection of differences in dementia/AD incidence.

MAPT (ClinicalTrials.gov identifier NCT00672685) is a French multicenter RCT evaluating
the efficacy of isolated supplementation with ω-3 fatty acid, isolated multidomain
intervention, or their combination in the prevention of cognitive decline in frail
individuals who are at least 70 years old. One thousand six hundred eighty community-dwelling
participants have been enrolled by using a frailty definition that includes three
components: presence of memory complaints, limitation in one instrumental activity
of daily living, and slow walking speed. The 3-year multidomain intervention consists
of group training sessions (physical exercise, cognitive training, and nutritional
advice) and yearly personalized preventive consultations that aim to identify dementia
and frailty risk factors (vascular risk factors, nutritional problems, sensory deficits,
mood disorders, and walking difficulties) and promote their management in collaboration
with the general practitioner. Follow-up is 5 years, and the main outcome measure
is the 3-year change in cognitive function assessed with a neuropsychological test
(Grober and Buschke) [48,50].

The PreDIVA study (Controlled-Trials.com identifier ISRCTN29711771) is a Dutch multicenter,
open, cluster RCT comparing standard and intensive care of cardiovascular risk factors
in preventing dementia and disability in older people. The study includes 3,534 communitydwellers
who are 70 to 78 years old and who were recruited from primary care practices. The
standard care is based on guidelines for Dutch general practice, whereas the multicomponent
intensive vascular care addresses hypertension, hypercholesterolemia, smoking habits,
excessive weight, physical inactivity, and diabetes mellitus, which are strictly controlled
with medication and lifestyle interventions. Study duration is 6 years, and primary
outcomes are incident dementia assessed according to standard criteria and disability
as measured with the Academic Medical Center Linear Disability Scale [49].

Researchers involved in these large European trials (FINGER, MAPT, and PreDIVA) recently
started the European Dementia Prevention Initiative (EDPI), an international collaboration
to improve preventive strategies against dementia [51]. Collaboration and data sharing within the EDPI will allow refining of methodological
aspects of prevention trials, including identification of target populations, improvement
of intervention methods (that is, type, intensity, and duration), and development
and standardization of relevant outcome measures and prognostic and monitoring tools
that can be easily implemented in large populations. This will help planning larger,
international prevention trials able to provide robust evidence on dementia/AD prevention.

Conclusions

Although the pathogenesis of dementia is not fully elucidated, primary prevention
seems possible as most factors involved in dementia onset and progression are modifiable
or amenable to management. The recent AHRQ/NIH report shows that development of successful
preventive strategies requires a more refined knowledge of risk and protective factors
for dementia and AD as well as a validation of the observational studies with large
intervention studies [7]. AD and VaD share several risk factors, and most dementia cases are attributable
to both vascular and neurodegenerative brain damage. Furthermore, population-based
neuropathological studies have shown that both subclinical neurodegenerative (amyloid
plaques, neurofibrillary tangles, and Lewy bodies) and vascular lesions (and their
co-occurrence) are common in the brains of cognitively normal older individuals [52]. In light of this, preventive strategies aiming to postpone the onset of dementia
syndrome have great potential.

Epidemiological research suggests that the most effective strategy may be to encourage
the implementation of multiple preventive measures throughout the life course, including
high educational attainment in childhood and early adulthood, active control of vascular
factors and disorders over adulthood, and maintenance of mentally, physically, and
socially active lifestyles during middle age and later in life. It has been estimated
that half of AD cases worldwide are potentially attributable to modifiable risk factors,
and a 10% to 25% reduction in these factors could potentially prevent 3 million AD
cases worldwide, and a reduction in all risk factors would have the greatest impact
on dementia prevalence [21]. However, RCTs are indispensable to confirm the effect of risk reduction strategies
targeting multiple risk factors. Multidomain interventional RCTs are ongoing and will
provide new insights into prevention of cognitive impairment and dementia. Full implementation
of the lifecourse approach is more challenging because of the difficulties of carrying
out RCTs over many decades. Such long-term studies would require very large sample
sizes and huge financial resources, and a pragmatic way to assess the effect of long-term
interventions within an RCT has not yet been established. Furthermore, for ethical
reasons, several risk and protective factors are not appropriate for intervention
trials. Thus, evidence about these factors relies on conducting rigorous observational
studies (for example, placebo-controlled trials for high blood pressure or cholesterol
are not possible, because such treatments are known to protect against cardiovascular/cerebrovascular
diseases) [9]. Methodological alternatives to RCTs have been proposed to obtain robust evidence
on AD and dementia prevention [11,53]. The ongoing RTCs on dementia prevention will have to take into account the 'window
of opportunity hypothesis' when evaluating the results of interventions. In fact,
efficacy of preventive actions may vary by age. Thus, implementation of interventions
at the appropriate time in the life course is crucial for successful prevention. Refining
of prognostic tools, which can be used for early detection of subjects at risk of
dementia in the general population, will also help to better plan intervention studies.
Also, when older individuals are targeted, the frequent coexistence of chronic diseases
needs to be considered since it can negatively impact cognitive performance and limit
adherence to preventive interventions. On the other hand, appropriate management of
morbidity can help improve cognitive performance and delay dementia onset. For instance,
although stroke is a known risk factor for dementia, it has been recently reported
that about 25% of stroke patients discontinued one or more of their prescribed secondary
prevention medications within 3 months of hospitalization for acute stroke [54-56]. Improving long-term adherence to poststroke treatment can prevent recurrent cerebrovascular
diseases and contribute to preventing or delaying clinical expression of dementia
syndrome. Additionally, there is evidence of inadequate management of hypertension
and hypercholesterolemia in older adults [49]. Similar situations exist for heart failure, which increases the risk of dementia
among older adults [56], and diabetes mellitus, which accelerates the progression from mild cognitive impairment
to dementia by more than 3 years [57]. Preliminary results from the PreDIVA study showed that 87% of the study participants
have at least one modifiable risk factor amenable to intervention, proving the presence
of a window of opportunity for improved risk management [49].

In conclusion, prevention of dementia is now moving from observational to interventional
studies to verify hypotheses and define tools that can be applied in the general population.
Epidemiological and preclinical studies will continue to provide new information on
risk/protective factors and pathological mechanisms. The international collaboration
among research teams involved in ongoing multidomain RCTs will allow the sharing of
experiences and discussions on methodological aspects of these studies. This can help
in interpretation of results, identification and solution of problems related to intervention
strategies, and refinement of preventative approaches.

Since a cure for dementia is not yet available, finding effective preventive strategies
is essential for a sustainable society in an aging world. As dementia, cardiovascular
diseases, stroke, and diabetes mellitus - all major public health problems - share
several risk factors, public health efforts promoting a healthier lifestyle have the
potential to enhance health status in advanced age.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

This study was supported by Karolinska Institutet (Sweden), the Swedish Research Council
for Medical Research, the Academy of Finland, the La Carita Foundation of Finland,
the Alzheimer's Association (USA), and the Swedish Foundations of Ragnhild och Einar
Lundströms-Minne-Lindhés, Stohnes-Stiftelse, and Gamla-Tjänarinnor. The funding sources
did not play any role in the design or conduct of the study or in the collection,
management, analysis, or interpretation of data or in the preparation, review, or
approval of the manuscript. Editor Kimberly Kane revised the language in the manuscript.